Lowering blood sugar with novel 4-thienyl-dihydropyridines

ABSTRACT

Blood sugar levels are reduced by administration of novel 4-thienyl-dihydropyridines of the formula ##STR1## in which R 1  represents 1 or 2 halogen atoms, or represents straight-chain, branched or cyclic alkyl with up to 8 carbon atoms, 
     R 2  represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical which has up to 15 carbon atoms, is optionally interrupted by one or two oxygen atoms, -N-phenyl or --SO n  -- (n=0, 1 or 2) and is optionally substituted by halogen, phenyl, hydroxyl, cyano, amino, C 1  -C 6  -alkylamino, di-C 1  -C 6  -alkylamino, pyridyl, piperidino, N-phenylpiperazino, N-methylpiperazino, morpholino or N-benzyl-N-methyl-amino, 
     R 3  represents hydrogen, or represents straight-chain, branched or cyclic alkyl which has up to 6 carbon atoms and is optionally substituted by halogen, hydroxyl, amino or amino-C 1  -C 6  -alkoxy, or represents cyano or formyl and 
     R 4  represents hydrogen or a straight-chain, branched or cyclic alkyl radical which has up to 10 carbon atoms, is optionally interrupted by one or two oxygen atoms in the chain and is optionally substituted by halogen, cyano, hydroxyl, phenyl, carboxyl, C 1  -C 6  -alkoxycarbonyl, amino, C 1  14 C 6  -alkylamino, di-C 1  -C 6  -alkylamino, formyl, piperidino, morpholino or thiomorpholino, or physiologically acceptable salts thereof.

This is a division of application Ser. No. 937,870, filed Dec. 4, 1986,now U.S. Pat. No. 4,801,715.

The invention relates to 4-thienyl-dihydropyridine-lactones, processesfor their preparation and their use in medicaments, in particular inmedicaments which influence the blood sugar.

The present invention relates to 4-thienyl-dihydropyridines of thegeneral formula (I) ##STR2## in which R¹ represents 1 or 2 halogenatoms, or represents straight-chain, branched or cyclic alkyl with up to8 carbon atoms,

R² represents a straight-chain, branched or cyclic, saturated orunsaturated hydrocarbon radical which has up to 15 carbon atoms, isoptionally interrupted by one or two oxygen atoms, --N-phenyl or--SO_(n) -- (n=0, 1 or 2) and is optionally substituted by halogen,phenyl, hydroxyl, cyano, amino, C₁ -C₆ -alkylamino, di-C₁ -C₆-alkylamino, pyridyl, piperidino, N-phenylpiperazino,N-methylpiperazino, morpholino or N-benzyl-N-methyl-amino,

R³ represents hydrogen, or represents straight-chain, branched or cyclicalkyl which has up to 6 carbon atoms and is optionally substituted byhalogen, hydroxyl, amino or amino-C₁ -C₆ -alkoxy, or represents cyano orformyl and

R⁴ represents hydrogen or a straight-chain, branched or cyclic alkylradical which has up to 10 carbon atoms, is optionally interrupted byone or two oxygen atoms in the chain and is optionally substituted byhalogen, cyano, hydroxyl, phenyl, carboxyl, C₁ -C₆ -alkoxycarbonyl,amino, C₁ -C₆ -alkylamino, di-C₁ -C₆ -alkylamino, formyl, piperidino,morpholino or thiomorpholino,

in the form of their isomers, isomer mixtures, racemates and opticalantipodes and their physiologically acceptable salts.

Compounds of the formula (I) which are of particular interest are thosein which

R¹ represents 1 or 2 fluorine, chlorine or bromine atoms, or representsstraight-chain or branched alkyl with up to 6 carbon atoms,

R² represents a straight-chain, branched or cyclic saturated orunsaturated hydrocarbon radical which has up to 10 carbon atoms, isoptionally interrupted by one or two oxygen atoms or by N-phenyl and isoptionally substituted by one or more fluorine, chlorine, bromine,phenyl, hydroxyl, cyano, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄-alkylamino, N-phenylpiperazino or N-benzyl-N-methylamino groups,

R³ represents cyano, or represents straight-chain or branched alkylwhich has up to 4 carbon atoms and is optionally substituted byfluorine, chlorine, bromine, hydroxyl or amino-C₁ -C₄ -alkoxy and

R⁴ represents hydrogen or a straight-chain, branched or cyclic alkylradical which has up to 8 carbon atoms, is optionally interrupted by oneor two oxygen atoms in the chain and is optionally substituted by one ormore fluorine, chlorine, bromine, cyano, phenyl, carboxyl, C₁ -C₄-alkoxycarbonyl, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino ormorpholino groups,

in the form of their isomers, isomer mixtures, racemates and opticalantipodes, and their physiologically acceptable salts.

Compounds of the formula (I) which are of very particular interest arethose in which

R¹ represents fluorine or chlorine, or represents straight-chain orbranched alkyl with up to 4 carbon atoms,

R² represents a straight-chain, branched or cyclic hydrocarbon radicalwhich has up to 8 carbon atoms, is optionally interrupted by an oxygenatom and is optionally substituted by one or more fluorine, chlorine,phenyl, hydroxyl, cyano, amino, C₁ -C₃ -alkylamino, di-C₁ -C₃-alkylamino or N-benzyl-N-methyl-amino groups,

R³ represents C₁ -C₄ -alkyl which is optionally substituted by hydroxyland

R⁴ represents hydrogen, or represents a straightchain, branched orcyclic alkyl radical with up to 6 carbon atoms,

in the form of their isomers, isomer mixtures, racemates and opticalantipodes, and their physiologically acceptable salts.

Compounds of the formula (I) which may be mentioned in particular arethose in which

R¹ represents chlorine or C₁ -C₄ -alkyl,

R² represents a straight-chain or branched alkyl radical with up to 6carbon atoms,

R³ represents C₁ -C₄ -alkyl and

R⁴ represents hydrogen or an alkyl radical with up to 4 carbon atoms,

in the form of their isomers, isomer mixtures, racemates and opticalantipodes and their physiologically acceptable salts.

The substances according to the invention can exist in the form of theirsalts. These are in general salts of the substances according to theinvention with inorganic or organic acids. However, the physiologicallyacceptable salts of the substances according to the invention withinorganic or organic acids are preferred. Examples which may bementioned are: hydrohalides, bisulphates, sulphates, hydrogenphosphates, acetates, maleates, citrates, fumarates, tartrates, lactatesor benzoates.

The compounds according to the invention exist in stereoisomeric formswhich either behave as mirror images (enantiomers) or do not behave asmirror images (diastereomers). The invention relates both to theantipodes and to the racemic forms as well as diastereomer mixtures. Theracemic forms, like the diastereomers, can be resolved into thestereoisomerically pure constituents in a known manner (compare E. L.Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

The compounds of the general formula (I) according to the invention canbe prepared by a process in which

[A] aldehydes of the general formula II ##STR3## in which R¹ has themeaning given,

are reacted with acetoacetic acid esters of the general formula III##STR4## in which R² and R³ have the abovementioned meaning,

and with enamines of the general formula IV ##STR5## in which R⁴ has themeaning given,

in inert solvents, or by a process in which

[B] ylidene compounds of the general formula V ##STR6## in which R¹, R²and R³ have the meaning given,

are reacted with enamines of the formula IV in inert solvents, or by aprocess in which

[C] dihydropyridinelacetones of the general formula VI ##STR7## in whichR¹ to R³ have the meaning given,

are treated with bases in inert solvents and then alkylated withcompounds of the general formula VII

    R.sup.4 --X                                                VII

in which

R⁴ has the meaning given and

X represents halogen, preferably chlorine, bromine or iodine, orrepresents a diazo group, or represents a group of the formula --O--SO₂R⁵,

wherein

R⁵ has the meaning of R⁴ or represents phenyl, or tolyl.

The processes can be illustrated by the following equations, dependingon the nature of the starting substances used: ##STR8##

Possible solvents for processes A and B are all the organic solventswhich do not change under the reaction conditions. These include,preferably, alcohols, such as methanol, ethanol, propanol orisopropanol, or ethers, such as diethyl ether, dioxane, tetrahydrofuranor glycol monomethyl or dimethyl ether, dimethylformamide, acetic acid,actonitrile, pyridine, dimethylsulphoxide or hexamethylphosphoric acidtriamide. It is also possible to use mixtures of the solvents mentioned.

Possible solvents for process C are the customary inert organicsolvents. These include, preferably, ethers, such as diethyl ether,dioxane or tetrahydrofuran, or acid amides, such as dimethylformamide orhexamethylphosphoric acid triamide, or dimethylsulphoxide or sulpholane,or hydrocarbons, such as benzene, xylene, toluene, hexane or petroleumfractions.

The bases customary for deprotonation can be used as the bases (processC). These include, preferably, alkali metal hydrides, such as sodiumhydride or potassium hydride, or alkali metal amides, such as sodiumamide, potassium diethylamide or lithium diisopropylamide, or alkalimetal hydroxides, such as potassium hydroxide or sodium hydroxide,alkali metal alcoholates, such as potassium tert.-butanolate, potassiummethylate or potassium ethylate, or metal-organyls, such asphenyllithium, n-butyllithium or tert.-butyllithium.

The reaction temperatures can be varied within a substantial range inprocesses A and B. The reaction is in general carried out in a rangefrom +10° C. to +200° C., preferably from +20° C. to +150° C.

The reaction of the dihydropyridinelactone VI with the base (process C)is in general carried out in a temperature range from -20° C. to +180°C. and particularly preferably from 20° C. up to the boiling point ofthe solvent used.

All the processes can be carried out under normal, increased or reducedpressure. They are in general carried out under normal pressure.

The aldehydes of the formula II used as starting substances are known orcan be prepared by known methods (compare U.S. Pat. No. 2,601,479; U.S.Pat. No. 2,853,493; and J. prakt. Chem. 1964, 64).

The acetoacetic acid esters of the formula III used as startingsubstances are known or can be prepared by known methods (compare D.Borrmann, Houben-Weyl "Methoden der organischen Chemie" ("Methods ofOrganic Chemistry") Volume VII 14, 230 et seq.).

The enamines of the formula IV used as starting substances are known orcan be prepared by known methods (compare European Patent 123,095).

The ylidene compounds of the formula V used as starting substances areknown or can be prepared by known methods (compare G. Jones, "TheKnoevenagel Condensation", Organic Reactions XV, 204 (1967)).

The dihydropyridinelactones of the formula VI used as startingsubstances are new in some cases. However, they can be prepared by knownmethods (DOS (German Published Specification) 3,205,399).

The compounds of the formula I according to the invention display auseful pharmacological action spectrum. With only a slight action on thecirculation, they reduce the blood sugar and can thus be used for thetreatment of diabetes.

The hypoglycaemic action of the substances to be investigated was testedon male Wistar rats weighing between 140 and 190 g. For this purpose,the rats were weighed 18 hours before administration of the substancesand were divided into groups of 6 animals and fasted. The substances tobe investigated were suspended in aqueous 0.75% strength tragacanthsuspension using an Ultra-Turrax directly before the administration. Thetragacanth suspension (control animals) or the substances suspended intragacanth were administered by means of a stomach tube.

Blood was withdrawn from each rat from the retro-orbital venous plexus30, 60 and 120 minutes after the administration. Portions of 32 μl ofblood were taken with an automatic diluter and deproteinated with 0.3 mlof uranyl acetate (0.16% strength). After the centrifugation, theglucose in the supernatant was determined photometrically on a GemsaecFast Analyzer by the glucose oxidase method with 4-amino-phenazone asthe color reagent. The results were evaluated by the student t-test,p<0.05 being chosen as the significance limit.

Substances which effected a significant reduction of the blood glucoseconcentration in the rats of at least 10% at a point in time incomparison with the control group which received only tragacanthsuspension were described as active.

The following Table 1 contains the changes found in the blood glucoseconcentrations in percent of the control.

                  TABLE 1                                                         ______________________________________                                                       Decrease in the blood glucose                                                 concentration in % of the                                      Substance      control                                                        (Patent Example No.)                                                                         10 mg/kg p.o.                                                  ______________________________________                                        2              21                                                             5              25                                                             6              13                                                             ______________________________________                                    

The present invention includes pharmaceutical formulations whichcontain, in addition to non-toxic, inert pharmaceutically suitableexcipients, one or more active compounds according to the invention orwhich consist of one or more active compounds according to theinvention, and processes for the preparation of these formulations.

The present invention also includes pharmaceutical formulations indosage units. This means that the formulations are present in the formof individual parts, for example tablets, dragees, capsules, pills,suppositories and ampules, the active compound content of whichcorrespond to a fraction or a multiple of an individual dose. The dosageunits can contain, for example, 1, 2, 3 or 4 individual doses or 1/2,1/3 or 1/4 of an individual dose. An individual dose preferably containsthe amount of active compound which is given in one administration andwhich usually corresponds to a whole, one half, one third or one quarterof a daily dose.

By non-toxic, inert pharmaceutically suitable excipients there are to beunderstood solid, semi-solid or liquid diluents, fillers and formulationauxiliaries of all types.

Tablets, dragees, capsules, pills, granules, suppositories, solutions,suspensions and emulsions, pastes, ointments, gels, creams, lotions,powders and sprays may be mentioned as preferred pharmaceuticalformulations.

Tablets, dragees, capsules, pill and granules can contain the activecompound or compounds in addition to the customary excipients, such as(a) fillers and extenders, for example starches, lactose, sucrose,glucose, mannitol and silicic acid, (b) binders, for examplecarboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone,(c) humectants, for example glycerol, (d) disintegrating agents, forexample agar-agar, calcium carbonate and sodium bicarbonate, (e)solution retarders, for example paraffin, and (f) absorptionaccelerators, for example quaternary ammonium compounds (g) wettingagents, for example cetyl alcohol and glycerol monostearate, (h)adsorbents, for example kaolin and betonite, and (i) lubricants, forexample talc, calcium stearate, magnesium stearate and solidpolyethylene glycols, or mixtures of the substances listed under (a) to(i).

The tablets, dragees, capsules, pills and granules can be provided withthe customary coatings and shells, if appropriate containing opacifyingagents, and can also be of such composition that they release the activecompound or compounds only or preferentially in a certain part of theintestinal tract, if appropriate in a delayed manner, examples ofembedding compositions which can be used being polymeric substances andwaxes.

The active compound or compounds can also be in microencapsulated form,if appropriate with one or more of the abovementioned excipients.

Suppositories can contain, in addition to the active compound orcompounds, the customary water-soluble or water-insoluble excipients,for example polyethylene glycols, fats, for example cocoa fat, andhigher esters (for example C₁₄ -alcohol with C₁₆ -fatty acid), ormixtures of these substances.

Ointments, pastes, creams and gels can contain, in addition to theactive compound or compounds, the customary excipients, for exampleanimal and vegetable fats, waxes, paraffins, starch, tragacanth, silicicacid, talc and zinc oxide, or mixtures of these substances.

Powders and sprays can contain, in addition to the active compound orcompounds, the customary excipients, for example lactose, talc, silicicacid, aluminium hydroxide, calcium silicate and polyamide powder, ormixtures of these substances, and sprays can additionally contain thecustomary propellants, for example chlorofluorohydrocarbons.

Solutions and emulsions can contain, in addition to the active compoundor compounds, the customary excipients, such as solvents, solubilizingagents and emulsifiers, for example water, ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide,oils, in particular cottonseed oil, groundnut oil, maize germ oil, oliveoil, castor oil and sesame oil, glycerol, glycerol formal,tetrahyrofurfuryl alcohol, polyethylene glycols and fatty acid esters ofsorbitan, or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also bein a sterile form which is isotonic with blood.

Suspensions can contain, in addition to the active compound orcompounds, the customary excipients, such as liquid diluents, forexample water, ethyl alcohol and propylene glycol, and suspendingagents, for example ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances.

The formulation forms mentioned can also contain colouring agents,preservatives and additives which improve the smell and taste, forexample peppermint oil and eucalyptus oil, and sweeteners, for examplesaccharin.

The therapeutically active compounds should preferably be present in theabovementioned pharmaceutical formulations in a concentration of about0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also contain otherpharmaceutical active compounds in addition to the active compoundsaccording to the invention.

The abovementioned pharmaceutical formulations are prepared in thecustomary manner by known methods, for example by mixing the activecompound or compounds with the excipient or excipients.

The present invention also includes the use of the compounds of theformula I and/or salts thereof and of pharmaceutical formulationscontaining the compounds of the formula I and/or salts thereof in humanand veterinary medicine for preventing, alleviating and/or healing theabovementioned diseases.

The active compounds or the pharmaceutical formulations can beadministered orally, parenterally, intraperitoneally and/or rectally,preferably orally and parenterally.

In general, it has proved advantageous both in human and in veterinarymedicine to administer the active compound or compounds according to theinvention in total amounts of about 0.01 to about 200 mg/kg, preferably0.1 to 50 mg/kg of body weight every 24 hours, if appropriate in theform of several individual administrations, to achieve the desiredresults.

However, it may be necessary to deviate from the dosages mentioned, andin particular to do so as a function of the nature and body weight ofthe subject to be treated, the nature and severity of the diseases, thenature of the formulation and of the administration of the medicamentand the period or interval within which administration takes place. Thusit can in some cases suffice to manage with less than the abovementionedamount of active compound, while in other cases the abovementionedamount of active compound must be exceeded. The particular optimumdosage required and mode of administration of the active compounds caneasily be specified by any expert on the basis of his expert knowledge.

Preparation Examples EXAMPLE 1 Isopropyl4-(3-chloro-2-thienyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]-pyridine-3-carboxylate##STR9##

40 mmol of 3-chloro-thiophene-2-carbaldehyde, 40 mmol of3-acetoxyacetoacetic acid ester and 40 mmol of isopropyl3-aminocrotonate are boiled under reflux over NaOH in EtOH, alcoholichydrochloric acid is then added and the mixture is boiled for 1 hour. Itis concentrated and the residue is crystallized.

Yield: 50% of theory.

Melting point: 194°-5° C.

EXAMPLE 2 Isopropyl4-(3-chloro-2-thienyl)-1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate##STR10##

10 mmol of isopropyl4-(3-chloro-2-thienyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3.4-b]pyridine-3-carboxylateare dissolved in 25 ml of dimethylformamide and deprotonated with NaH,and 20 mmol of ethyl iodide are added. After the mixture has beenstirred at room temperature for 1 hour, it is concentrated, water isadded to the residue and the product is filtered off with suction andrecrystallized from methanol.

Yield: 75% of theory.

Melting point: 76°-80° C.

The following compounds were prepared analogously to Example 1:

EXAMPLE 3 Isopropyl4-(2-chloro-3-thienyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate##STR11##

Yield: 40% of theory.

Melting point: 200°-202° C.

EXAMPLE 4 Isopropyl2-methyl-4-(3-methyl-2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate##STR12##

Yield: 15% of theory.

Melting point: 207°-8° C.

The following compounds were prepared analogously to Example 2:

EXAMPLE 5 Isopropyl4-(2-chloro-3-thienyl)-1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3.4-b]pyridine-3-carboxylate##STR13##

Yield: 45% of theory.

Melting point: 140°-5° C.

EXAMPLE 6 Isopropyl1-ethyl-2-methyl-4-(3-methyl-2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3.4-b]pyridine-3-carboxylate##STR14##

Yield: 40% of theory.

Melting point: 88°-93° C.

EXAMPLE 7 Isopropyl1,2-dimethyl-4-(3-methyl-2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate##STR15##

Yield: 60% of theory.

Melting point: 170°-4° C.

It is understood that the specification and examples are illustrativebut not limitative of the present invention and that other embodimentswithin the spirit and scope of the invention will suggest themselves tothose skilled in the art.

We claim:
 1. A 4-thienyl-dihydropyridine of the formula ##STR16## inwhich R¹ represents fluorine or chlorine, or represents straight-chainor branched alkyl with up to 4 carbon atoms,R² represents astraight-chain, branched or cyclic hydrocarbon radical which has up to 8carbon atoms, is optionally interrupted by an oxygen atom and isoptionally substituted by one or more fluorine, chlorine, phenyl,hydroxyl, cyano, amino, C₁ -C₃ -alkylamino, di-C₁ -C₃ -alkylamino orN-benzyl-N-methyl-amino groups, R³ represents C₁ -C₄ -alkyl which isoptionally substituted by hydroxyl and R⁴ represents methyl orstraight-chain, branched or cyclic alkyl radical with 3 to 6 carbonatoms,or a physiologically acceptable salt thereof.
 2. A4-thienyl-dihydropyridine or salt according to claim 1 in whichR¹represents chlorine or C₁ -C₄ -alkyl, R² represents a straight-chain orbranched alkyl radical with up to 6 carbon atoms, R³ represents C₁ -C₄-alkyl and R⁴ represents an alkyl radical with 1, 3 or 4 carbon atoms.3. A compound according to claim 1, wherein such compound is isopropyl1,2-dimethyl-4-(3-methyl-2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylateof the formula ##STR17## or a physiologically acceptable salt thereof.4. A blood-sugar lowering composition comprising a diluent and ablood-sugar lowering effective amount of a compound or salt according toclaim
 1. 5. A unit dose of a composition according to claim 4 in theform of a tablet, capsule or ampoule.
 6. A method of lowering the sugarcontent of a patient's blood comprising administering to such patient ablood-sugar lowering effective amount of a compound or salt according toclaim
 1. 7. The method according to claim 6, wherein such compound isisopropyl1,2-dimethyl-4-(3-methyl-2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate,or a physiologically acceptable salt thereof.